The present invention relates to substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines of general formula 1 
wherein
R1 and R2 which may be identical or different denote hydrogen, C1-C6-alkyl, C1-C6-alkyloxy, OH, F, Cl, or Br;
R3 may denote hydrogen, F, Cl, Br, methyl, ethyl, OH, or methoxy;
R4, R5, and R6, which may be identical or different, may denote hydrogen, methyl, or ethyl;
X may denote NH2, NHxe2x80x94(C1-C6-alkyl), N(C1-C6-alkyl)2, the two C1-C6-alkyl groups of which may be identical or different, NHxe2x80x94COH, NHxe2x80x94CO(C1-C6-alkyl), or F;
A may denote xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94CH(C1-C6-alkyl)-Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, 
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred compounds are those of general formula 1, wherein:
R1 and R2 which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl, or Br;
R3 may denote hydrogen, F, methyl, ethyl, OH, or methoxy;
R4, R5, and R6, which may be identical or different, may denote hydrogen or methyl;
X may denote NH2, NH-(methyl), N(methyl)2, NH-(ethyl), N(ethyl)2, NHxe2x80x94COH, NHxe2x80x94COMe, or F;
A may denote xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH(methyl)-Oxe2x80x94CH2xe2x80x94, xe2x80x94CH(ethyl)-Oxe2x80x94CH2xe2x80x94, xe2x80x94CH(isopropyl)-Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)4xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, 
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are compounds of general formula 1, wherein:
R1 and R2 which may be identical or different, may denote hydrogen or F;
R3 may denote hydrogen or methyl;
R4, R5, and R6, which may be identical or different, may denote hydrogen or methyl;
X may denote NH2, NH-(methyl), N(methyl)2, NHxe2x80x94COH, or NHxe2x80x94COMe;
A may denote xe2x80x94CH(methyl)-Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or 
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of comparable importance according to the invention are compounds of general formula 1 wherein:
R1 and R2 which may be identical or different may denote hydrogen or F;
R3 may denote hydrogen;
R4, R5, and R6, which may be identical or different, may denote hydrogen or methyl;
X may denote F;
A may denote xe2x80x94CH(methyl)-Oxe2x80x94CH2xe2x80x94,
optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of particular interest are compounds of general formula 1 selected from the group comprising:
(2R,6S,2Sxe2x80x2)-10-amino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S,2Sxe2x80x2)-10-amino-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S,11R,2xe2x80x3S)-10-amino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S,11S,2xe2x80x3S)-10-amino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S)-10-amino-3-[2(2,6-difluorophenylmethoxy)ethyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S,2xe2x80x3S,5xe2x80x3S)-10-amino-3-[5xe2x80x3-phenyltetrahydrofuran-2xe2x80x3-yl)methyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S,2xe2x80x3S)-10-acetamino-3-[2(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride;
(2R,6S,2xe2x80x3S)-10-acetamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride;
(2R,6S,2xe2x80x3S)-10-formylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine hydrochloride;
(2R,6S,2xe2x80x3S)-10-methylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride;
(2R,6S,2xe2x80x3S)-10-dimethylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride; and
(2R,6S,2xe2x80x3S)-10-ethylamino-3-[2(2,6-difluorophenylmethoxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine dihydrochloride.
C1-C6-alkyl denotes a branched or unbranched hydrocarbon group having 1 to 6 carbon atoms which may optionally also contain ring systems. The alkyl substituents may be identical or different and may optionally be substituted with one or more halogen atoms, preferably fluorine. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some cases, common abbreviations are also used for the abovementioned alkyl groups, such as, for example, Me for methyl, Et for ethyl, prop for propyl, etc.
According to the invention, the double-bonded groups representing group A may be linked to the adjacent groups in both possible orientations.
If desired, the compounds of general formula 1 may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable acid addition salts thereof with an inorganic or organic acid. Suitable acids for this purpose include, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid, or citric acid. Mixtures of the abovementioned acids may also be used.
The compounds according to the invention are blockers of the voltage-dependent sodium channel. They are compounds which competitively or non-competitively displace batrachotoxin (BTX) with a high affinity (Ki less than 1000 nM) from the binding site on the sodium channel. Such substances exhibit xe2x80x9cuse-dependencyxe2x80x9d in blocking the sodium channels, i.e., in order for the substances to bind to the sodium channel the sodium channels first have to be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels. Consequently, the substances preferentially bind to sodium channels which are activated repeatedly.
As a result, the substances are capable of acting preferentially in those parts of the body which are pathologically overstimulated. This includes diseases such as arrhythmias, spasms, cardiac and cerebral ischaemia, pain and neurodegenerative diseases of various origins. The following may be mentioned, for example: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotrophic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, and local anesthesia.
Another aspect of the invention therefore relates to the use of compounds of general formula 1 as pharmaceutical compositions, particularly as pharmaceutical compositions in which the blockade of the voltage-dependent sodium channel may have a therapeutic value.
The compounds of general formula 1 according to the invention are preferably used to prepare a pharmaceutical composition for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischemias, pain, and neurodegenerative disorders.
The compounds of general formula 1 according to the invention are most preferably used as hereinbefore to prepare pharmaceutical compositions for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotrophic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain, and local anesthesia.
The test system used to detect the blocking effect on the sodium channel is the BTX binding to the sodium channel [S. W. Postma and W. A. Catterall, Mol. Pharmacol., 25, 219-227 (1984)] and patch-clamp experiments which can be used to show that the compounds according to the invention block the electrically stimulated sodium channel in a xe2x80x9cuse-dependentxe2x80x9d manner [W. A. Catterall, Trends Pharmacol. Sci., 8, 57-65 (1987)]. The effect of the substances on various subtypes of sodium channel can be investigated by suitable selection of the cell system (e.g., neuronal, cardiac, DRG cells).
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blockade of the veratridine-induced glutamate release [S. Villanueva, P. Frenz, Y. Dragnic, and F. Orrego, Brain Res., 461, 377-380 (1988)]. Veratridine is a toxin which permanently opens the sodium channel. As a result, there is an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx in the neuronal tissue leads to an increased glutamate release. The compounds according to the invention will antagonize this glutamate release.
The anticonvulsant properties of the substances according to the invention have been demonstrated by their protective effect against convulsions induced by a maximum electric shock in mice [M. A. Rogawski and R. J. Porter, Pharmacol. Rev., 42, 223-286 (1990)].
Neuroprotective properties have been demonstrated by the protective effect in a rat-MCAO model [U. Pschorn and A. J. Carter, J. Stroke Cerebrovascular Diseases, 6, 93-99 (1996)], a malonate-induced lesion model [M. F. Beal, Annals of Neurology, 38, 357-366 (1995) and J. B. Schulz, R. T. Matthews, D. R. Henshaw, and M. F. Beal, Neuroscience, 71, 1043-1048 (1996)] and an MPTP-induced degeneration model [J. P. Steiner, et al Proc. Natl. Acad. Sci., 94, 2019-2024 (1997)].
The analgesic effect was shown in a formalin-induced pain model [D. Dubuisson and S. G. Dennis, Pain, 4, 161-174 (1977)] and in a ligature model [G. J. Bennett and Y.-K. Xie, Pain, 33, 87-107 (1988)].
It has also been shown that sodium channel blockers can be used to treat cyclophrenia (manic depressive disease) [J. R. Calabrese, C. Bowden, and M. J. Woyshville, in: Psychopharmacology: The Fourth Generation of Progress (Eds. D. E. Bloom and D. J. Kupfer) 1099-1111, New York: Raven Press Ltd.].
The compounds according to the invention 1 may be prepared analogously to methods of synthesis known per se. One possible method of synthesis is shown in Diagram 1. The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols (2) designated as starting compounds in Diagram 1 may be obtained by methods of synthesis known from the art. In connection with this, reference is made at this point to European Patent Application EP 521422 and to International Patent Applications WO 97/06146 and WO 99/14199. 
The key step is the conversion of the phenol 2 into the corresponding amino compound 1xe2x80x2 (corresponding to compounds 1 wherein X is NH2), which is done by means of a Buchwald reaction [J. P. Wolfe, J. Ahman, J. P. Sadighi, R. A. Singer, and S. L. Buchwald, THL 1997, 6367-6370].
The triflates 3 required for this reaction may be prepared from these compounds 2 with trifluoromethanesulfonic acid anhydride in the presence of an auxiliary base. Suitable auxiliary bases according to the invention include organic amines such as, for example, dimethylaminopyridine, pyridine, or tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine, or DBU (diazabicycloundecene). Of the abovementioned amines, the tertiary amines are preferably used, and triethylamine is most preferably used as the auxiliary base. The reaction is carried out in aprotic, organic solvents, preferably in solvents selected from among dimethylformamide, dimethylacetamide, methylene chloride, toluene, or tetrahydrofuran. Methylene chloride should be mentioned as being particularly preferred. The reactions to form the triflates 3 are preferably carried out at temperatures below ambient temperature, more preferably at xe2x88x9250xc2x0 C. to 0xc2x0 C., most preferably at between xe2x88x9230xc2x0 C. and xe2x88x925xc2x0 C. After 0.5 to 4 hours, stirring is continued at ambient temperature until the reaction is complete (about 1 to 12 hours). After working up, the crude products 3 thus obtained are reacted, without further purification, in an aromatic organic solvent, preferably selected from among toluene, benzene, or xylene, most preferably toluene, with palladium as catalyst, preferably in the presence of a phosphine ligand, with a nitrogen source, preferably with ketimines, most preferably with benzophenonimine. Suitable palladium catalysts according to the invention include tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, or tetrakis(triphenylphosphine)palladium(0), for example. Suitable phosphine ligands which may be used include, for example, ligands selected from among DPPF, BINAP, p-tolBINAP, PPh2-CHMe-P(tBu)2, phosphine-substituted ferrocenes, or triphenylphosphine. Tris(dibenzylideneacetone)dipalladium/BINAP is preferably used as the catalyst system. The reaction is preferably carried out with the exclusion of moisture and oxygen and preferably at elevated temperature. The solvent used is preferably refluxed during the reaction.
The imine adduct obtained as an intermediate can be converted by acid hydrolysis, preferably with dilute inorganic acids, most preferably with dilute hydrochloric acid, into the compounds according to the invention 1xe2x80x2 (corresponding to compounds of formula 1 where X is NH2). The products are purified by chromatography on silica gel or by crystallization, preferably by crystallization of the pharmacologically acceptable acid addition salts, e.g., the hydrochlorides.
As can be seen from the above remarks, the triflates of general formula 3 are of central importance in the synthesis of the compounds of general formula 1 according to the invention.
Accordingly, another aspect of the present invention relates to the intermediate compounds of general formula 3 
wherein the groups R1, R2, R3, R4, R5, R6, and A may be as hereinbefore defined.
In order to synthesize the compounds according to the invention of general formula 1 where X is not NH2, the following process may be used.
Compounds of formula 1 wherein X is NHxe2x80x94(C1-C6)-alkyl or N(C1-C6-alkyl)2 may be obtained by methods known per se by alkylation of 1xe2x80x2, by reductive amination or by acylation, optionally in the presence of organic bases, with subsequent reduction.
For alkylation, the following method may be used. A compound of general formula 1xe2x80x2 is dissolved in a polar organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, or tetrahydrofuran, preferably dimethylformamide or methylene chloride. The resulting solution is mixed with a base and a corresponding alkylating agent. Suitable bases include alkali and alkaline earth metal hydrides, preferably sodium hydride. Suitable alkylating agents include alkyl halides, such as alkyl chloride, alkyl bromide, particularly alkyl iodide and alkyl tosylates, mesylates, triflates, and dialkylsulfates. After conventional working up, the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallization, optionally in the form of the pharmacologically acceptable addition salts thereof, preferably as hydrochlorides.
In order to prepare the compounds of general formula 1 by reductive amination, the amines 1xe2x80x2 are mixed with aldehydes or ketones in the presence of acids such as dilute hydrochloric acid, dilute acetic acid, or dilute sulfuric acid, under otherwise conventional reaction conditions, with cooling, preferably at xe2x88x9250xc2x0 C. to ambient temperature, most preferably between xe2x88x9230xc2x0 C. and 0xc2x0 C., and the Schiff bases or iminium salts thus formed as intermediates are then reduced. The reduction is carried out using metal hydrides such as sodium borohydride, LiAlH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, or NaBH(OAc)3; sodium borohydride is preferably used. After working up in the usual way, the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallization, optionally in the form of their pharmacologically acceptable acid addition salts thereof, preferably as hydrochlorides.
Compounds of formula 1 where X is NHCO(C1-C6-alkyl) may be prepared by methods known per se by acylating 1xe2x80x2, preferably with acid chlorides or anhydrides. For this, the amino compound of formula 1xe2x80x2 is suspended in an organic solvent, combined with an organic base and the desired acid chloride or anhydride is added. The mixture is kept at ambient temperature for 40 to 60 minutes, preferably 25 to 45 minutes at ambient temperature. Suitable organic solvents are dimethylformamide, dimethylacetamide, methylene chloride, toluene, or tetrahydrofuran; methylene chloride being preferred. Suitable organic bases are dimethylaminopyridine, pyridine, or tertiary amines, e.g., trimethylamine, triethylamine, diisopropylethylamine, and DBU (diazabicycloundecene). After working up, the products are purified by chromatography on silica gel or by crystallization, preferably by crystallization of the pharmacologically acceptable acid addition salts, e.g., the hydrochlorides.
Starting from the compounds of formula 1 with X is NHCO(C1-C6-alkyl) which may be obtained by the method described above, compounds of formula 1 with X is NH(C1-C6-alkyl), for example, may also be obtained by reduction with metal hydrides such as LiAlH4, Li-alkoxyhydrides, NaBH4, NaBHCN3, or NaBH(OAc)3, preferably sodium borohydride. These reactions are preferably carried out in ethereal organic solvents, preferably in tetrahydrofuran or dioxane in the presence of Lewis acids, preferably boron trifluoride etherate, at elevated temperature, preferably above 50xc2x0 C., most preferably at the reflux temperature of the solvent used. After working up, the products are purified by chromatography on silica gel or by crystallization, preferably by crystallization of the pharmacologically acceptable acid addition salts, e.g., the hydrochlorides.
The formylated compounds of formula 1 (Xxe2x95x90NHCOH) may be obtained, for example, by reacting the compounds of formula 1xe2x80x2 with formic acid at elevated temperature, preferably at reflux temperature. After working up, the products are purified by chromatography on silica gel or by crystallization, preferably by crystallization of the pharmacologically acceptable acid addition salts, e.g., the hydrochlorides.
The fluorine-substituted compounds 1 (with X is F) may be obtained by methods known per se by diazotization of 1xe2x80x2 and subsequent decoction with BF4xe2x88x92. Preferably, the reaction is carried out with NOBF4 as the diazotization and fluorination reagent in ethereal solvents, preferably in tetrahydrofuran or dioxane at elevated temperature, preferably above 50xc2x0 C., most preferably at the reflux temperature of the solvent used. After working up, the products are purified by chromatography on silica gel or by crystallization, preferably by crystallization of the pharmacologically acceptable acid addition salts, e.g., the hydrochlorides.